Previous research emphasizes pleiotropic effects of the APOE 19q13.3 region variants supporting protective (notably, the APOE e2 allele) and detrimental (the APOE e4 allele) roles in Alzheimer?s disease (AD) and aging. Despite nearly two-decade progress in the APOE research, however, even pathogenic role of the strongest risk factor for AD, the APOE e4 allele, remains poorly understood. Understanding protective role of the e2 allele is lagged behind the APOE e4 research due to, in part, seemingly smaller effects of this allele on AD. This paradoxical situation of a potentially strong role of the APOE locus in AD and aging, and a hampered progress in the ApoE2-Aging-AD research requires new approaches. Our approach is built on core principles of evolutionary biology in genetics of aging- related traits characteristic for post-reproductive life, insights from genetic epidemiology of such traits, and the results of our large-scale pilot study of five human cohorts proving its significance and feasibility. The core of our approach is the association of AD with complex molecular signatures in the APOE region, rather than with a single allele, which include the e2 allele. These signatures are defined by significant differences in linkage disequilibrium (LD) patterns between affected and unaffected subjects. The principal difference between our approach and previous studies of LD structures in the APOE region, making it highly innovative, is that following the core biological principles in genetics of aging- related traits, the effects in the ApoE2-Aging-AD framework are considered to be associated with AD- specific molecular signatures, rather than with those driven by common evolutionarily forces. This difference justifies the focus on extended signatures comprised of the APOE e2 allele and SNPs spread through the entire genome and interacting with this allele. Analysis of molecular signatures provides invaluable opportunity to dissect heterogeneity in action of the APOE e2 allele by identifying personalized (i.e., more homogeneous, group specific) polygenic profiles with stronger protective effect of this allele. The objective of this proposal is to identify personalized polygenic profiles, comprised of the e2 allele, other SNPs in the APOE region, and SNPs spread through the entire genome, with stronger protection in the ApoE2-Aging-AD framework, and identify the role of AD risk factors in these profiles. Specific aims: Aim 1. Identify molecular signatures of AD and life span as a proxy for aging. Aim 2. Dissect heterogeneity and identify commonalities in the molecular signatures. Aim 3. Identify personalized polygenic profiles of AD and aging traits. Aim 4. Use bioinformatics analysis to characterize functional consequences of SNPs and genes.